There are a large number of diseases which are caused by disordered metabolism of lipid, sugar, protein, or endocrine substances. In healthy people, the levels of these substances in the body are generally maintained at constant levels, and excessive amounts of these substances are actively excreted via specific metabolism routes. However, if a specific metabolism route is disordered for a certain reason, a substance to be metabolized is circulated and accumulated in the body, causing an increase in the level of the substance and a variety of diseases. One example of such diseases is hyperlipidemia, which involves an abnormal increase in level of serum lipid (mainly cholesterol, triglyceride, phospholipid, and free fatty acids). Hyperlipidemia is categorized according to the standards. When the fasting serum LDL cholesterol level is 140 mg/dL or higher, this condition is defined as hyper-LDL-cholesterolemia, and when the fasting triglyceride level is 150 mg/dL or higher, this condition is defined as hyper-triglyceridemia. Particularly, hyper-LDL-cholesterolemia is thought to be a main cause for coronary diseases and cerebrovascular disorders, and occurrence of these diseases is reduced by controlling the blood LDL cholesterol level, supported by sufficient evidence.
The treatment of hyperlipidemia employs various drugs such as statin drugs, fibrate drugs, nicotinic acid, anion-exchange resin, cholesterol absorption inhibitors, probucol, dextran sulfate, and ethyl icosapentate. Recently, statin drugs such as pravastatin, sinvastatin, fluvastatin, atorvastatin, pitavastatin, and rosuvastatin are mainly employed in the treatment. Among statin drugs, pitavastatin or a salt thereof is known to exhibit intense HMG-CoA reductase inhibitory effect and serve as a useful blood cholesterol level lowering agent (Patent Document 1). According to the Japan Arteriosclerosis Society Guidelines, the target LDL cholesterol level of a patient is determined in accordance with the number of risk factors for arteriosclerosis of the patient. When a statin is employed in a high-risk group, only about 25% of the patients can clear the target level. Homo-type familial hypercholesterolemia is a type of hereditary disease involving defect of an LDL receptor gene. Since a statin drug works by the action mechanism of activating the LDL receptor, the treatment by statin is no longer effective for a patient of this type. Generally, blood LDL (low-density lipoprotein) is incorporated into the liver by the mediation of the LDL receptor which is present on the surface of liver parenchyama cells, and an excessive amount of LDL is excreted as bile. The patients of homo-type familial hypercholesterolemia have a defect in this function. In addition, the serum cholesterol level is as high as 600 to 1,000 mg/dL, and arteriosclerosis progresses from early childhood, resulting in juvenile heart infarction.
For the treatment of this disease, there have been carried out clinical trials of the gene therapy in which the deficient LDL receptor gene is incorporated. However, the safety of such gene therapy has not yet been established, and many problems to be solved remain for practical employment of the gene therapy. Another possible alternative therapy is liver transplantation. However, since the liver function itself of the patient is normal, liver transplantation is ethically problematic and not realistic therapy. Thus, such severe hypercholesterolemia patients are treated through LDL apheresis, which is a technique in which blood is caused to flow through a column which specifically adsorbs LDL (dextran sulfate cellulose column), to thereby selectively adsorb LDL for removal. The technique can be performed for a long period of time with high safety. However, since LDL apheresis is a plasma exchange technique based on extracorporal circulation, a patient of an age under 5 or 6 cannot receive the therapy. Therefore, arteriosclerosis progressing from the birth of the patient cannot be treated. In addition, cost of the therapy is very high, and the physical load of the therapy is heavy to the patient. Thus, from the viewpoint of enhancement of QOL of the patient, it is desired to establish a new therapy.
For certain reasons, in the patients which undergo blood dialysis, there are observed, in the body, disordered metabolism of water and electrolytes, accumulation of various nitrogen metabolites, and kidney-related hormone abnormality. Generally, substances toxic to the body are excreted through the kidneys, the liver, the gastrointestinal tract, etc. In renal failure patients, excretion of toxic substances through the kidneys requires a longer time, which aggravates renal function disorders and adversely affects other organs. In some cases, the renal failure is fatal.
In the above case, continuous ambulatory peritoneal dialysis and blood dialysis are most generally employed as alternative treatments. According to the statistics of Japan Society for Dialysis Therapy (as of the end of December, 2004), chronic patients requiring dialysis numbers 248,166, and the number of survivals over 20 years is 15,899 (6.7%), with the longest dialysis history of the patients being 37 years and 3 months.
As the period of dialysis becomes longer, dialysis amyloidosis is actually observed as a complication. In renal failure patients, excretion of β2 microglobulin (middle-size protein) is impeded by failure and disorders of renal functions, resulting in high blood β2 microglobulin level. Accumulation of β2 microglobulin causes dialysis amyloidosis. As a result, amyloid fiber deposits in the entire body of an dialysis amyloidosis patient, leading to disorders of bones, nerves, and joints, involving pain and numbness. In this case, QOL of the patient is considerably deteriorated.
In the treatment of dialysis amyloidosis, β2 microglobulin, which is a causal substance, is removed. From the early stage, there have been employed a dialysis technique of high β2 microglobulin removal performance, hemodialysisfiltration (HDF), and a dialyzer having a dialysis membrane having a large pore size (high-performance membrane). Online HDF has gradually come to be employed, in which plasma is actively extracted from blood, and an almost equivolume of liquid replacement is perfused, thereby purifying dialysis liquid during perfusion. If the condition of the patient is grave, surgical treatment is carried out. Cost of these therapies is very high, and the physical load of such a therapy is heavy to the patient. Thus, from the viewpoint of enhancement of QOL of the patient, it is desired to establish a new therapy.
Meanwhile, an auxiliary tool for enhancing the therapeutic effect of a medical column for extracorporeal circulation is also employed. Specifically, hexadecyl-group-immobilized cellulose beads (Lixelle, registered trademark), which specifically bind to β2 microglobulin, is employed (Patent Document 2). It has also been reported that joint pain and the like of dialysis amyloidosis patients are mitigated through hemoadsorption employing hexadecyl-group-immobilized cellulose beads. However, these auxiliary tools for enhancing the therapeutic effect of a medical column for extracorporeal circulation must be used in combination with an anti-clotting agent, or the medical column for extracorporeal circulation must be imparted with an antithrombotic property. Use of an anti-clotting agent imposes a load to the patients, and some patients exhibit shock conditions upon use of heparin, which is a widely employed anti-clotting agent. Therefore, it is desired to establish a new therapy.
In the therapy of a severe hyperlipidemia patient, the therapy of removing an excessive amount of a substance occurring in the body due to certain metabolic disorders, excretion failure, difficulty in removal, etc. (e.g., removal of LDL and removal of β2 microglobulin from dialysis amyloidosis patients), hemodialysis and various apheresis techniques are generally carried out. However, as described above, these methods involve problems of QOL of the patients and high medical cost. Therefore, there is keen demand for new therapeutic means replacing hemodialysis and various apheresis therapeutic techniques.
Idiopathic dilated cardiomyopathy (DCM) is a chronic and progressive disease which involves considerable dilation of the heart lumen, resulting in myocardial contraction failure and which has bad prognosis with a clinical picture showing congestive heart failure. According to an investigation carried out in 1999 by the Ministry of Health and Welfare, the number of patients in Japan was estimated to 17,700. However, since there are many subclinical patients, the actual number is thought to be greater than 17,700.
At present, one radical therapeutic method for DCM is typically heart transplantation in which the heart is transplanted from a brain-death donor. In Japan, the concept “brain death” is not widely accepted by people, and heart transplantation is not often performed. Throughout the world, the number of heart donors is smaller than the patients requiring heart transplantation, which is problematic. Since heart transplantation is not supported by the medical security system, the patient who undergoes transplantation is charged a high medical fee, even when a heart donor has been found. Furthermore, if transplantation is successfully complete, the patient must take an immuno-suppressor for the rest of his or her life. Therefore, the patient is susceptible to suffer an infection disease due to the suppressed immune system, which is a severe problem. Thus, as medical therapy, an angiotensin-converting enzyme inhibitor and a β-blocker are administered in combination to the target patients, and good therapeutic results are obtained (Non-Patent Document 1). However, in some cases the expected effect fails to be attained, depending on the body constitution and progress of the disease condition. In addition, since the medical therapy can only retard the progress of the disease, there is keen demand for therapeutic means for radically treating DCM based on medical therapy.    Patent Document 1: JP-A-1989-279866    Patent Document 2: JP-A-1997-266948    Non-Patent Document 1: Med. J. Aust., 2001, 174, 459-466